tbuckley/cabot-search huggingface dataset:
Π-Π interactions stabilize PeptoMicelle-based formulations of Pretomanid derivatives leading to promising therapy against tuberculosis in zebrafish and mouse models
Authors: Nils-Jørgen K. Dal, Gabriela Schäfer, Andrew M. Thompson, Sascha Schmitt, Natalja Redinger, Noelia Alonso-Rodriguez, Kerstin Johann, Jessica Ojong, Jens Wohlmann, Andreas Best, Kaloian Koynov, Rudolf Zentel, Ulrich E. Schaible, Gareth Griffiths, Matthias Barz, Federico Fenaroli
Journal: Journal of Controlled Release (2023)

Tuberculosis is the deadliest bacterial disease globally, threatening the lives of millions every year. New antibiotic therapies that can shorten the duration of treatment, improve cure rates, and impede the development of drug resistance are desperately needed. Here, we used polymeric micelles to encapsulate four second-generation derivatives of the antitubercular drug pretomanid that had previously displayed much better in vivo activity against Mycobacterium tuberculosis than pretomanid itself. Because these compounds were relatively hydrophobic and had limited bioavailability, we expected that their micellar formulations would overcome these limitations, reduce toxicities, and improve therapeutic outcomes. The polymeric micelles were based on polypept(o)ides (PeptoMicelles) and were stabilized in their hydrophobic core by π-π interactions, allowing the efficient encapsulation of aromatic pretomanid derivatives. The stability of these π-π-stabilized PeptoMicelles was demonstrated in water, blood plasma, and lung surfactant by fluorescence cross-correlation spectroscopy and was further supported by prolonged circulation times of several days in the vasculature of zebrafish larvae. The most efficacious PeptoMicelle formulation tested in the zebrafish larvae infection model almost completely eradicated the bacteria at non-toxic doses. This lead formulation was further assessed against Mycobacterium tuberculosis in the susceptible C3HeB/FeJ mouse model, which develops human-like necrotic granulomas. Following intravenous administration, the drug-loaded PeptoMicelles significantly reduced bacterial burden and inflammatory responses in the lungs and spleens of infected mice.
Delivery of macromolecules in unstimulated T cells by photoporation with polydopamine nanoparticles
Authors: Dominika Berdecka, Aranit Harizaj, Ilia Goemaere, Deep Punj, Glenn Goetgeluk, Stijn De Munter, Herlinde De Keersmaecker, Veerle Boterberg, Peter Dubruel, Bart Vandekerckhove, Stefaan C. De Smedt, Winnok H. De Vos, Kevin Braeckmans
Journal: Journal of Controlled Release (2023)
MRSA lineage USA300 isolated from bloodstream infections exhibit altered virulence regulation
Authors: Sophie Dyzenhaus, Mitchell J. Sullivan, Bremy Alburquerque, Daiane Boff, Adriana van de Guchte, Marilyn Chung, Yi Fulmer, Richard Copin, Juliana K. Ilmain, Anna O’Keefe, Deena R. Altman, François-Xavier Stubbe, Magdalena Podkowik, Amy C. Dupper, Bo Shopsin, Harm van Bakel, Victor J. Torres
Journal: Cell Host & Microbe (2023)

The epidemic community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 lineage has recently become a leading cause of hospital-associated bloodstream infections (BSIs). Here, we leveraged this recent introduction into hospitals and the limited genetic variation across USA300 isolates to identify mutations that contribute to its success in a new environment. We found that USA300 BSI isolates exhibit altered virulence regulation. Using comparative genomics to delineate the genes involved in this phenotype, we discovered repeated and independent mutations in the transcriptional regulator sarZ. Mutations in sarZ resulted in increased virulence of USA300 BSI isolates in a murine model of BSI. The sarZ mutations derepressed the expression and production of the surface protein ClfB, which was critical for the pathogenesis of USA300 BSI isolates. Altogether, these findings highlight ongoing evolution of a major MRSA lineage and suggest USA300 strains can optimize their fitness through altered regulation of virulence.
Complementary medicine and phospholipase A2 receptor (PLA2R)–related membranous nephropathy—fortuitous or causal?
Authors: Prabhjot Kaur, Arun Prabhahar, Ashwani Kumar, Deeksha Pal, Vinod Kumar, Aravind Sekar, Vivekanand Jha, Ritambhra Nada, Jasmine Sethi, Smita Divyaveer, Manish Rathi, Harbir Singh Kohli, Raja Ramachandran
Journal: Kidney International (2023)
Changing the Focus in the Donation After Circulatory Death Debates
Authors: Jason N. Batten, Rosemary O’Meeghan, Pedro A. Catarino, Michael Nurok, Miriam Piven Cotler
Journal: The American Journal of Bioethics (2023)

"Changing the Focus in the Donation After Circulatory Death Debates." The American Journal of Bioethics, 23(2), pp. 48–49
Micropapillary and Solid Histologic Patterns in N1 and N2 Lymph Node Metastases Are Independent Factors of Poor Prognosis in Patients With Stages II to III Lung Adenocarcinoma
Authors: Yan Li, Alexander J. Byun, Jennie K. Choe, Shaohua Lu, David Restle, Takashi Eguchi, Kay See Tan, Jasmeen Saini, James Huang, Gaetano Rocco, David R. Jones, William D. Travis, Prasad S. Adusumilli
Journal: Journal of Thoracic Oncology (2023)
Corrigendum to “Magnetic Resonance Imaging and targeted biopsies compared to transperineal mapping biopsies prior to salvage focal therapy/ablation in localised and metastatic recurrent prostate cancer after radiotherapy. Primary Outcomes from the FORECAST Trial” [Eur Urol 2022;81(6):598–605]
Authors: Taimur T. Shah, Abi Kanthabalan, Marjorie Otieno, Menelaos Pavlou, Rumana Omar, Sola Adeleke, Francesco Giganti, Chris Brew-Graves, Norman R. Williams, Jack Grierson, Haroon Miah, Amr Emara, Athar Haroon, Arash Latifoltojar, Harbir Sidhu, Joey Clemente, Alex Freeman, Clement Orczyk, Ashok Nikapota, Tim Dudderidge, Richard G. Hindley, Jaspal Virdi, Manit Arya, Heather Payne, Anita Mitra, Jamshed Bomanji, Mathias Winkler, Gail Horan, Caroline M. Moore, Mark Emberton, Shonit Punwani, Hashim U. Ahmed
Journal: European Urology (2023)
Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRG/RTOG 0912): a randomised, double-blind, placebo-controlled, multicentre, phase 2 trial
Authors: Eric J Sherman, Jonathan Harris, Keith C Bible, Ping Xia, Ronald A Ghossein, Christine H Chung, Nadeem Riaz, G Brandon Gunn, Robert L Foote, Sue S Yom, Stuart J Wong, Shlomo A Koyfman, Michael F Dzeda, David A Clump, Saad A Khan, Manisha H Shah, Kevin Redmond, Pedro A Torres-Saavedra, Quynh-Thu Le, Nancy Y Lee
Journal: The Lancet Oncology (2023)
Causal role of a neural system for separating and selecting multidimensional social cognitive information
Authors: Ali Mahmoodi, Hamed Nili, Caroline Harbison, Sorcha Hamilton, Nadescha Trudel, Dan Bang, Matthew F.S. Rushworth
Journal: Neuron (2023)

People are multi-faceted, typically good at some things but bad at others, and a critical aspect of social judgement is the ability to focus on those traits relevant for the task at hand. However, it remains unknown how the brain supports such context-dependent social judgement. Here, we examine how people represent multidimensional individuals, and how the brain extracts relevant information and filters out irrelevant information when comparing individuals within a specific dimension. Using human fMRI, we identify distinct neural representations in dorsomedial prefrontal cortex (dmPFC) and anterior insula (AI) supporting separation and selection of information for context-dependent social judgement. Causal evaluation using non-invasive brain stimulation shows that AI disruption alters the impact of relevant information on social comparison, whereas dmPFC disruption only affects the impact of irrelevant information. This neural circuit is distinct from the one supporting integration across, as opposed to separation of, different features of a multidimensional cognitive space.
Risk of early death in adolescents and young adults with cancer: a population-based study
Authors: Amy M Berkman, Clark R Andersen, Michelle A T Hildebrandt, J A Livingston, Adam L Green, Vidya Puthenpura, Susan K Peterson, Joel Milam, Kimberly A Miller, David R Freyer, Michael E Roth
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Advancements in treatment and supportive care have led to improved survival for adolescents and young adults (AYAs) with cancer; however, a subset of those diagnosed remain at risk for early death (within 2 months of diagnosis). Factors that place AYAs at increased risk of early death have not been well studied. Methods The Surveillance, Epidemiology, and End Results registry was used to assess risk of early death in AYAs with hematologic malignancies, central nervous system tumors, and solid tumors. Associations between age at diagnosis, sex, race, ethnicity, socioeconomic status, insurance status, rurality, and early death were assessed. Results A total of 268 501 AYAs diagnosed between 2000 and 2016 were included. Early death percentage was highest in patients diagnosed with hematologic malignancies (3.1%, 95% confidence interval [CI] = 2.9% to 3.2%), followed by central nervous system tumors (2.5%, 95% CI = 2.3% to 2.8%), and solid tumors (1.0%, 95% CI = 0.9% to 1.0%). Age at diagnosis, race, ethnicity, lower socioeconomic status, and insurance status were associated with increased risk of early death in each of the cancer types. For AYAs with hematologic malignancies and solid tumors, risk of early death decreased statistically significantly over time. Conclusions A subset of AYAs with cancer remains at risk for early death. In addition to cancer type, sociodemographic factors also affect risk of early death. A better understanding of the interplay of factors related to cancer type, treatment, and health systems that place certain AYA subsets at higher risk for early death is needed to address these disparities and improve outcomes.
The swan genome and transcriptome, it is not all black and white
Authors: Anjana C. Karawita, Yuanyuan Cheng, Keng Yih Chew, Arjun Challagulla, Robert Kraus, Ralf C. Mueller, Marcus Z. W. Tong, Katina D. Hulme, Helle Bielefeldt-Ohmann, Lauren E. Steele, Melanie Wu, Julian Sng, Ellesandra Noye, Timothy J. Bruxner, Gough G. Au, Suzanne Lowther, Julie Blommaert, Alexander Suh, Alexander J. McCauley, Parwinder Kaur, Olga Dudchenko, Erez Aiden, Olivier Fedrigo, Giulio Formenti, Jacquelyn Mountcastle, William Chow, Fergal J. Martin, Denye N. Ogeh, Françoise Thiaud-Nissen, Kerstin Howe, Alan Tracey, Jacqueline Smith, Richard I. Kuo, Marilyn B. Renfree, Takashi Kimura, Yoshihiro Sakoda, Mathew McDougall, Hamish G. Spencer, Michael Pyne, Conny Tolf, Jonas Waldenström, Erich D. Jarvis, Michelle L. Baker, David W. Burt, Kirsty R. Short
Journal: Genome biology (2023)

Abstract Background The Australian black swan ( Cygnus atratus ) is an iconic species with contrasting plumage to that of the closely related northern hemisphere white swans. The relative geographic isolation of the black swan may have resulted in a limited immune repertoire and increased susceptibility to infectious diseases, notably infectious diseases from which Australia has been largely shielded. Unlike mallard ducks and the mute swan ( Cygnus olor ), the black swan is extremely sensitive to highly pathogenic avian influenza. Understanding this susceptibility has been impaired by the absence of any available swan genome and transcriptome information. Results Here, we generate the first chromosome-length black and mute swan genomes annotated with transcriptome data, all using long-read based pipelines generated for vertebrate species. We use these genomes and transcriptomes to show that unlike other wild waterfowl, black swans lack an expanded immune gene repertoire, lack a key viral pattern-recognition receptor in endothelial cells and mount a poorly controlled inflammatory response to highly pathogenic avian influenza. We also implicate genetic differences in SLC45A2 gene in the iconic plumage of the black swan. Conclusion Together, these data suggest that the immune system of the black swan is such that should any avian viral infection become established in its native habitat, the black swan would be in a significant peril.
Pathometagenomics reveals susceptibility to intestinal infection by Morganella to be mediated by the blood group-related B4galnt2 gene in wild mice
Authors: Marie Vallier, Abdulhadi Suwandi, Katrin Ehrhardt, Meriem Belheouane, David Berry, Aleksa Čepić, Alibek Galeev, Jill M. Johnsen, Guntram A. Grassl, John F. Baines
Journal: Gut Microbes (2023)

Infectious disease is widely considered to be a major driver of evolution. A preponderance of signatures of balancing selection at blood group-related genes is thought to be driven by inherent trade-offs in susceptibility to disease. B4galnt2 is subject to long-term balancing selection in house mice, where two divergent allele classes direct alternative tissue-specific expression of a glycosyltransferase in the intestine versus blood vessels. The blood vessel allele class leads to prolonged bleeding times similar to von Willebrand disease in humans, yet has been maintained for millions of years. Based on in vivo functional studies in inbred lab strains, it is hypothesized that the cost of prolonged bleeding times may be offset by an evolutionary trade-off involving susceptibility to a yet unknown pathogen(s). To identify candidate pathogens for which resistance could be mediated by B4galnt2 genotype, we here employed a novel "pathometagenomic" approach in a wild mouse population, which combines bacterial 16S rRNA gene-based community profiling with histopathology of gut tissue. Through subsequent isolation, genome sequencing and controlled experiments in lab mice, we show that the presence of the blood vessel allele is associated with resistance to a newly identified subspecies of Morganella morganii, a clinically important opportunistic pathogen. Given the increasing importance of zoonotic events, the approach outlined here may find useful application in the detection of emerging diseases in wild animal populations.
The outcomes of patients with chronic myeloid leukemia treated with third‐line <scp>BCR</scp>::<scp>ABL1</scp> tyrosine kinase inhibitors
Authors: Elias J. Jabbour, Koji Sasaki, Fadi G. Haddad, Ghayas C. Issa, Guillermo Garcia‐Manero, Tapan M. Kadia, Nitin Jain, Musa Yilmaz, Courtney D. DiNardo, Keyur P. Patel, Rashmi Kanagal‐Shamanna, Richard Champlin, Issa F. Khouri, Sara Dellasala, Sherry A. Pierce, Hagop Kantarjian
Journal: American Journal of Hematology (2023)

The BCR::ABL1 tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with chronic myeloid leukemia (CML). After failing second-generation TKI (2G-TKI), the optimal third-line therapy in chronic phase CML (CML-CP) is not well established. We analyzed 354 patients with CML-CP treated with a third-line BCR::ABL1 TKI at our institution, and in the PACE and OPTIC trials, and evaluated the outcome after alternate 2G-TKIs or ponatinib. We performed a propensity score matching analysis to compare outcomes and multivariate analysis to identify variables associated with survival. One hundred seventy-three (49%) patients received 2G-TKIs and 181 (51%) ponatinib. Patients in the ponatinib group had more cardiovascular risk factors (34% versus 19%) and higher disease burden (BCR::ABL1 transcript levels >1%, 165/175 [94%] versus 75/135 [55%]; p < .001) compared with the 2G-TKI group. Among the 173 evaluable patients treated with ponatinib, 89 (52%) achieved 2 + -log reduction of baseline transcripts (20% 2-log reduction and 32% 3 + -log reduction). Among the 128 evaluable patients treated with 2G-TKIs, 44 (34%) achieved 2 + -log reduction of baseline transcripts (13% 2-log reduction and 21% 3 + -log reduction). With a median follow-up of 46 months, the 3-year progression-free survival was 59% (60% before matching) with 2G-TKI and 83% (81% before matching) with ponatinib (p < .001). The 3-year survival was 83% (81% before matching) with 2G-TKI and 87% (89% before matching) with ponatinib (p = .03). By multivariate analysis, third-line therapy with ponatinib was the only independent factor associated with better survival (p = .003). In conclusion, ponatinib is an optimal treatment for patients with CML-CP failing two prior TKIs.
Complement‐driven hemolytic uremic syndrome
Authors: Juliette Leon, Marie‐Bénédicte LeStang, Rebecca Sberro‐Soussan, Aude Servais, Dany Anglicheau, Véronique Frémeaux‐Bacchi, Julien Zuber
Journal: American Journal of Hematology (2023)

Overactivation of the complement alternative pathway drives the pathogenesis of primary atypical hemolytic uremic syndrome (aHUS). Genetically-determined or acquired dysregulation of the complement is frequently identified in patients with aHUS, pregnancy-related hemolytic uremic syndrome (HUS), and severe hypertension-associated HUS. In contrast, it is still unclear whether self-limited complement activation, which frequently occurs in other forms of HUS, provides key mechanistic clues or results from endothelial damage. Development of novel biomarkers is underway to firmly establish complement-driven pathogenesis. C5 blockade therapy has revolutionized the management of aHUS patients, resulting in a halving of the subpopulation under chronic dialysis over the course of a few years. On the other hand, the efficacy of C5 blockade in secondary forms of HUS, as assessed by small and uncontrolled case series, is less compelling and should be investigated through properly designed prospective clinical trials. The increased risk of meningococcal infection, related to C5 inhibition, must be rigorously addressed with suitable prophylaxis. Treatment duration should be determined based on an individualized benefit/risk assessment.
Humoral and cellular responses after COVID-19 booster vaccination in patients recently treated with anti-CD20 antibodies
Authors: Masashi Nishikubo, Yoshimitsu Shimomura, Ryusuke Yamamoto, Satoshi Yoshioka, Hayato Maruoka, Seiko Nasu, Tomomi Nishioka, Kenji Sakizono, Satoshi Mitsuyuki, Tomoyo Kubo, Naoki Okada, Daishi Nakagawa, Kimimori Kamijo, Hiroharu Imoto, Yuya Nagai, Nobuhiro Hiramoto, Noboru Yonetani, Tadakazu Kondo, Chisato Miyakoshi, Asako Doi, Takayuki Ishikawa
Journal: Blood Cancer Journal (2023)
Immunologic characterization of a patient with clinical and virologic rebound upon Nirmatrelvir/Ritonavir treatment: the unfortunate epilogue of COVID-19
Authors: Giulia Marchetti, Roberta Rovito, Valeria Bono, Paola Bonara, Francesca Bai, Antonella d’Arminio Monforte
Journal: Clinical Microbiology and Infection (2023)
Absent expansion of AXIN2+ hepatocytes and altered physiology in Axin2CreERT2 mice challenges the role of pericentral hepatocytes in homeostatic liver regeneration
Authors: Stephanie May, Miryam Müller, Callum R. Livingstone, George L. Skalka, Peter J. Walsh, Colin Nixon, Ann Hedley, Robin Shaw, William Clark, Johan Vande Voorde, Leah Officer-Jones, Fiona Ballantyne, Ian R. Powley, Thomas M. Drake, Christos Kiourtis, Andrew Keith, Ana Sofia Rocha, Saverio Tardito, David Sumpton, John Le Quesne, Martin Bushell, Owen J. Sansom, Thomas G. Bird
Journal: Journal of Hepatology (2023)

Mouse models of lineage tracing have helped to describe the important subpopulations of hepatocytes responsible for liver regeneration. However, conflicting results have been obtained from different models. Herein, we aimed to reconcile these conflicting reports by repeating a key lineage-tracing study from pericentral hepatocytes and characterising this Axin2CreERT2 model in detail.
Enhanced mitophagy driven by ADAR1-GLI1 editing supports the self-renewal of cancer stem cells in HCC
Authors: Jie Luo, Lanqi Gong, Yuma Yang, Yu Zhang, Qin Liu, Lu Bai, Xiaona Fang, Baifeng Zhang, Jiao Huang, Ming Liu, Beilei Liu, Ying Tang, Ching Ngar Wong, Jinlin Huang, Shan Liu, Shanshan Li, Tao Ding, Kwan Man, Victor Ho-Fun Lee, Yan Li, Stephanie Ma, Xin-Yuan Guan
Journal: Hepatology (2023)

Background and Aims: Deregulation of adenosine-to-inosine editing by adenosine deaminase acting on RNA 1 (ADAR1) leads to tumor-specific transcriptome diversity with prognostic values for HCC. However, ADAR1 editase-dependent mechanisms governing liver cancer stem cell (LCSC) generation and maintenance have remained elusive. Approach and Results: RNA-seq profiling identified ADAR1-responsive recoding editing events in HCC and showed editing frequency of GLI1 , rather than transcript abundance was clinically relevant. Functional differences in LCSC self-renewal and tumor aggressiveness between wild-type (GLI1 wt ) and edited GLI1 (GLI1 edit ) were elucidated. We showed that overediting of GLI1 induced an arginine-to-glycine (R701G) substitution, augmenting tumor-initiating potential and exhibiting a more aggressive phenotype. GLI1 R701G harbored weak affinity to SUFU, which in turn, promoted its cytoplasmic-to-nuclear translocation to support LCSC self-renewal by increased pluripotency gene expression. Moreover, editing predisposed to stabilize GLI1 by abrogating β-TrCP-GLI1 interaction. Integrative analysis of single-cell transcriptome further revealed hyperactivated mitophagy in ADAR1-enriched LCSCs. GLI1 editing promoted a metabolic switch to oxidative phosphorylation to control stress and stem-like state through PINK1-Parkin-mediated mitophagy in HCC, thereby conferring exclusive metastatic and sorafenib-resistant capacities. Conclusions: Our findings demonstrate a novel role of ADAR1 as an active regulator for LCSCs properties through editing GLI1 in the highly heterogeneous HCC.
COVID-19 vaccines versus pediatric hospitalization
Authors: Jaime S. Rosa Duque, Daniel Leung, Ka Man Yip, Derek H.L. Lee, Hung-kwan So, Wilfred H.S. Wong, Yu Lung Lau
Journal: Cell Reports Medicine (2023)

Vaccine effectiveness of BNT162b2 and CoronaVac against COVID-19-associated hospitalization and moderate-to-severe disease due to SARS-CoV-2 Omicron BA.2 is studied from the 1.36 million doses administered to 766,601 of 953,400 children aged 3-11 years and adolescents aged 12-18 years in Hong Kong as of April 2022. These vaccines confer substantial protection.